US8809553B2 - Process for the preparation of pteridine derivatives - Google Patents

Process for the preparation of pteridine derivatives Download PDF

Info

Publication number
US8809553B2
US8809553B2 US13/703,932 US201113703932A US8809553B2 US 8809553 B2 US8809553 B2 US 8809553B2 US 201113703932 A US201113703932 A US 201113703932A US 8809553 B2 US8809553 B2 US 8809553B2
Authority
US
United States
Prior art keywords
formula
compound
xii
arabinose
deoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US13/703,932
Other versions
US20130090474A1 (en
Inventor
Emanuele ATTOLINO
Mario Michieletti
Davide Rossi
Pietro Allegrini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dipharma Francis SRL
Original Assignee
Dipharma Francis SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dipharma Francis SRL filed Critical Dipharma Francis SRL
Assigned to DIPHARMA FRANCIS S.R.L. reassignment DIPHARMA FRANCIS S.R.L. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALLEGRINI, PIETRO, ATTOLINO, EMANUELE, Michieletti, Mario, ROSSI, DAVIDE
Publication of US20130090474A1 publication Critical patent/US20130090474A1/en
Application granted granted Critical
Publication of US8809553B2 publication Critical patent/US8809553B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/04—Seven-membered rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical

Definitions

  • the present invention relates to a novel process for the preparation of Sapropterin or a pharmaceutically acceptable salt thereof, and of novel synthetic intermediates thereof.
  • Sapropterin namely (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H) pteridinone, of formula (I), is the synthetic version of the 6R diastereomer of tetrahydrobiopterin (BH 4 ), the cofactor of phenylalanine hydrolase, the enzyme responsible for phenylalanine metabolism.
  • BH 4 tetrahydrobiopterin
  • the structure has three stereogenic centers, two in the dihydroxypropyl side chain and the third at the connection between the side chain and the pteridine ring (C-6).
  • the absolute configuration (R) at this center is required to obtain the desired pharmacological effects, as the 6S diastereomer can even induce the inactivation of phenylalanine hydrolase, thus inhibiting the effects of the 6R diastereomer.
  • Sapropterin as the polymorph anhydrous dihydrochloride salt, Form B is at present clinically used for the treatment of hyperphenylalaninaemia in patients suffering from phenylketonuria or BH4 deficiency.
  • Sapropterin herein referred to also as 6R-Sapropterin, is prepared (Scheme 1) by platinum-mediated catalytic hydrogenation of Biopterin of formula (II) or of derivatives thereof in which the amine and/or hydroxy functionalities are protected with conventional protective groups
  • the synthetic problem for the preparation of Sapropterin is to obtain L-biopterin of formula (II) on an industrial scale with a safe, efficient process.
  • the reducing sugar of formula (VI) is then converted to the corresponding acetylated phenylhydrazone of formula (VII) by treatment first with phenylhydrazine and then with acetic anhydride.
  • the compound of formula (VII) is then condensed with 6-hydroxy-2,4,5-triaminopyrimidine of formula (VIII) or a commercially available salt thereof, to give an adduct, which is not isolated but immediately subjected to oxidation to provide the acetylated biopterin of formula (IX).
  • 5-deoxy-L-arabinose of formula (VI) a non-natural reducing sugar, starting from L-rhamnose diethyl dithioacetal of formula (IV).
  • 5-Deoxy-L-arabinose of formula (VI) is indeed a key intermediate in the preparation of L-biopterin of formula (II) and therefore of Sapropterin.
  • Ethanethiol used in this preparation is a reagent widely known for the paramount environmental problem its use involves.
  • Ethanethiol has low boiling point (35° C.), and due to its disgusting odor that can be perceived even in a few ppm, is nowadays no longer used on an industrial scale, even in non-environmentally conscious, non-industrialized countries.
  • Low molecular alkylthiols similarly to ethanethiol, are in general toxic and because of their high volatility easily contaminate the operators and the environment.
  • a novel process has now been surprisingly found which provides 5-deoxy-L-arabinose of formula (VI) from a novel rhamnose dithioacetal of formula (XII), as herein defined.
  • the novel process overcomes the above reported mentioned problems, for instance with respect to dodecanethiol, it definitely involves a better atom economy and the thioglycoside impurity of formula (XI) or analogues thereof are not formed. Moreover it allows to obtain Sapropterin, or a pharmaceutically acceptable salt thereof, in very high yields, in a safer, efficient and reproducible manner without environmental problems on an industrial scale.
  • An object of the invention is therefore a process for the preparation of 5-deoxy-L-arabinose of formula (VI)
  • n 0, 1 or 2;
  • dithioacetal of formula (XII) to 5-deoxy-L-arabinose of formula (VI) can be carried out by a process comprising the oxidation of a dithioacetal of formula (XII) to obtain a disulfone of formula (XIII)
  • n is as defined above, and the subsequent reaction with a base.
  • the oxidation of a dithioacetal of formula (XII) can be carried out with an oxidizing agent for example selected from an organic peracid, preferably metachloro perbenzoic acid, periodic acid or a salt thereof, for example sodium periodate, a peroxysulfate, for example K 2 SO 5 , oxone, and hydrogen peroxide, optionally in the presence of a metal catalyst, for example sodium tungstate.
  • an organic peracid preferably metachloro perbenzoic acid, periodic acid or a salt thereof, for example sodium periodate, a peroxysulfate, for example K 2 SO 5 , oxone, and hydrogen peroxide, optionally in the presence of a metal catalyst, for example sodium tungstate.
  • reaction can be carried out in a solvent, which is selected depending on the oxidizing agent, as known to those skilled in the art.
  • a base which can be organic or inorganic, strong or weak, is preferably an amine, for example triethylamine or ammonia, more preferably ammonia.
  • the invention provides a process further comprising the conversion of 5-deoxy-L-arabinose of formula (VI), thus obtained, which can optionally be isolated, to L-biopterin of formula (II), or a salt thereof; and, if desired, the subsequent conversion of the latter to Sapropterin of formula (I) or a salt thereof.
  • a salt of L-biopterin of formula (II) or of Sapropterin of formula (I) is preferably a pharmaceutically acceptable salt thereof, for example a salt with an organic or inorganic acid, in particular with hydrochloric acid, typically the dihydrochloride.
  • the salification of L-biopterin of formula (II) or of Sapropterin of formula (I), as well as the conversion of said salts to the respective bases, can be carried out according to known methods.
  • a dithioacetal of formula (XII) can be prepared by a process comprising the reaction between L-rhamnose, for example commercial, anhydrous or hydrate, with a dithiol of formula (XIV)
  • n 0, 1 or 2
  • n is 0, 1 or 2
  • Dithiols of formula (XIV) are commercially available. Preferred are those in which n is 1 or 2. Such dithiols in which n is 1 or 2 have only 3 or 4 carbon atoms, like low alkyl thiols, but have higher boiling point, i.e. 169° C. or higher, moreover they do not have pungent smells in spite of their low number of carbon atoms. Thanks to this properties, in particular their low volatility, such dithiols are more suitable than other alkyldithiols for the use on an industrial scale.
  • a strong acid which can be organic or inorganic, is preferably a mineral acid, for example aqueous hydrochloric acid.
  • a solvent if present, can be a polar aprotic solvent, for example an amide, typically dimethylacetamide, dimethylsulfoxide or acetonitrile; a polar protic solvent, for example water or a C 1 -C 5 alkanol, an ether, for example tetrahydrofuran or dioxane, or a mixture of two or more, preferably 2 or 3, of them.
  • a polar aprotic solvent for example an amide, typically dimethylacetamide, dimethylsulfoxide or acetonitrile
  • a polar protic solvent for example water or a C 1 -C 5 alkanol
  • an ether for example tetrahydrofuran or dioxane, or a mixture of two or more, preferably 2 or 3, of them.
  • the reaction can be carried out at a temperature ranging from about 0° C. to the reflux temperature of the solvent, preferably around 20° C.
  • Dithioacetals of formula (XII) and disulfones of formula (XIII) are novel compounds and are a further object of the invention.
  • the invention provides a process for the preparation of Sapropterin, or a pharmaceutically acceptable salt thereof, which comprises the use of a compound of formula (XII), as herein defined, as the starting material.
  • L-Rhamnose monohydrate (168.3 g, 0.92 mol) is added as a solid in portions, under strong stirring, to a mixture of 1,3-propanedithiol (100 g, 0.92 mol) in 500 ml of 37% HCl.
  • the resulting solution is kept under stirring for 12 hours at about 20° C. Already at the first hour, formation of an abundant white precipitate is observed.
  • the suspension is then cooled to 5-10° C. and the acid excess is neutralized with NaOH and 500 ml of ice.
  • the suspension at pH of about 7 is then filtered and the solid is washed with water and 100 ml of isopropanol.
  • the wet solid is dried under vacuum at 40° C. for 16 hours to attain 222 g of product (XII) as an off-white solid in 95% yield.
  • the product is dried under vacuum at 50° C. for about 24 hours.
  • the suspension containing disulfone (XIII) from Example 2 is diluted with 1 liter of water and cooled to 10-15° C., then alkalinized to pH of 8-9 with 33% aqueous NH 3 .
  • a thick suspension immediately forms, which is kept under stirring for 16 hours at about 20° C., until complete disappearance of the starting product.
  • the solid is then filtered and washed with 250 ml of water.
  • the combined aqueous phases are extracted with ethyl acetate to remove any traces of sulfone.
  • the resulting 5-deoxy-(L)-arabinose (VI) aqueous solution can be used as such for the subsequent reaction to obtain L-biopterin and, if desired, Sapropterin.
  • the reaction mixture is maintained at about 20-25° C. for 1 hour till complete disappearence of the starting product.
  • the end-reaction suspension is then filtered and resulting solid is washed with water (215 g).
  • the bifase mixture obtained by filtration of the solid and containing 5-deoxy-(L)-arabinose (VI) can be used as such in the subsequent reaction to obtain L-biopterine and, if desired, Sapropterin.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catalysts (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The application discloses a process for the preparation of 5-deoxy-L-arabinose of formula (VI); comprising the conversion of a compound of formula (XII); wherein n is 0, 1 or 2; which can be used as intermediate for the synthesis of sapropterin.
Figure US08809553-20140819-C00001

Description

CROSS REFERENCE TO RELATED APPLICATION
This application is a 35 U.S.C. 371 National Phase Entry Application from PCT/EP2011/002896, filed Jun. 13, 2011, which claims the benefit of Italian Patent Application No. MI2010A001076 filed on Jun. 15, 2010, the disclosure of which is incorporated herein in its entirety by reference.
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Sapropterin or a pharmaceutically acceptable salt thereof, and of novel synthetic intermediates thereof.
TECHNOLOGICAL BACKGROUND
Sapropterin, namely (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H) pteridinone, of formula (I), is the synthetic version of the 6R diastereomer of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydrolase, the enzyme responsible for phenylalanine metabolism.
Figure US08809553-20140819-C00002
The structure has three stereogenic centers, two in the dihydroxypropyl side chain and the third at the connection between the side chain and the pteridine ring (C-6).
The absolute configuration (R) at this center is required to obtain the desired pharmacological effects, as the 6S diastereomer can even induce the inactivation of phenylalanine hydrolase, thus inhibiting the effects of the 6R diastereomer.
Sapropterin as the polymorph anhydrous dihydrochloride salt, Form B, is at present clinically used for the treatment of hyperphenylalaninaemia in patients suffering from phenylketonuria or BH4 deficiency.
Sapropterin, herein referred to also as 6R-Sapropterin, is prepared (Scheme 1) by platinum-mediated catalytic hydrogenation of Biopterin of formula (II) or of derivatives thereof in which the amine and/or hydroxy functionalities are protected with conventional protective groups
Figure US08809553-20140819-C00003
The hydrogenation reaction was reported for example in EP 0191335, which states that hydrogenation diastereoselectivity improves when the reaction is carried out in aqueous solution at basic pH under high hydrogen pressures.
Therefore, the synthetic problem for the preparation of Sapropterin is to obtain L-biopterin of formula (II) on an industrial scale with a safe, efficient process.
The synthesis of L-biopterin on an industrial scale is presently carried out starting from L-rhamnose of formula (III) (Scheme 2)
Figure US08809553-20140819-C00004
This synthesis involves the transformation of L-rhamnose monohydrate of formula (III), commercially available at extremely low prices, into its diethyl dithioacetal (IV) using ethanethiol both as reagent and solvent, in the presence of concentrated hydrochloric acid. Dithioacetal of formula (IV) is then oxidized with any known oxidizers to the corresponding disulfone of formula (V), which is then subjected to MacDonald-Fischer degradation under basic conditions, to provide 5-deoxy-L-arabinose of formula (VI) bearing the hydroxy functionalities of the desired absolute configuration, in aqueous solution. The reducing sugar of formula (VI) is then converted to the corresponding acetylated phenylhydrazone of formula (VII) by treatment first with phenylhydrazine and then with acetic anhydride. The compound of formula (VII) is then condensed with 6-hydroxy-2,4,5-triaminopyrimidine of formula (VIII) or a commercially available salt thereof, to give an adduct, which is not isolated but immediately subjected to oxidation to provide the acetylated biopterin of formula (IX). Basic or acid deacetylation of compound of formula (IX) yields biopterin of formula (II), which can either be isolated or maintained in solution, to be subjected to catalytic hydrogenation to provide Sapropterin of formula (I) as reported for example in above Scheme 1.
The main problem in the development of this process on an industrial scale is the preparation of 5-deoxy-L-arabinose of formula (VI), a non-natural reducing sugar, starting from L-rhamnose diethyl dithioacetal of formula (IV). 5-Deoxy-L-arabinose of formula (VI) is indeed a key intermediate in the preparation of L-biopterin of formula (II) and therefore of Sapropterin.
Ethanethiol used in this preparation is a reagent widely known for the paramount environmental problem its use involves. Ethanethiol has low boiling point (35° C.), and due to its disgusting odor that can be perceived even in a few ppm, is nowadays no longer used on an industrial scale, even in non-environmentally conscious, non-industrialized countries.
Low molecular alkylthiols, similarly to ethanethiol, are in general toxic and because of their high volatility easily contaminate the operators and the environment.
A possible solution to the problem was apparently the process disclosed in EP 1849793, which describes the preparation of L-rhamnose didodecyl dithioacetal, in yield of 75%, using dodecanethiol as the reagent. Dodecanethiol has in fact a C12 straight alkyl chain, is an inexpensive high boiling liquid, has the typical hydrocarbon odor and does not involve remarkable environmental problems, contrary to low-boiling, short chain thiols. We repeated the above described reaction, however, even when reaction parameters such as temperature, solvent, and the like were changed, it always provided (Scheme 3) mixtures of two products, namely the desired dithioacetal of formula (X) and thioglycoside of formula (XI) in nearly equimolar ratio, which are difficult to separate due to their amphiphilic nature. Therefore, the yield in the desired dithioacetal was always less than 50%. This is probably the reason why said European application has been abandoned.
Figure US08809553-20140819-C00005
Therefore, notwithstanding the efforts carried out to date to improve the synthesis of 5-deoxy-L-arabinose of formula (VI), there is still the need for an efficient, safe process for the preparation of L-biopterin of formula (II) and then Sapropterin of formula (I), or a salt thereof, on an industrial scale.
SUMMARY OF THE INVENTION
A novel process has now been surprisingly found which provides 5-deoxy-L-arabinose of formula (VI) from a novel rhamnose dithioacetal of formula (XII), as herein defined. The novel process overcomes the above reported mentioned problems, for instance with respect to dodecanethiol, it definitely involves a better atom economy and the thioglycoside impurity of formula (XI) or analogues thereof are not formed. Moreover it allows to obtain Sapropterin, or a pharmaceutically acceptable salt thereof, in very high yields, in a safer, efficient and reproducible manner without environmental problems on an industrial scale.
DETAILED DISCLOSURE OF THE INVENTION
An object of the invention is therefore a process for the preparation of 5-deoxy-L-arabinose of formula (VI)
Figure US08809553-20140819-C00006
comprising the conversion of a compound of formula (XII)
Figure US08809553-20140819-C00007
wherein n is 0, 1 or 2;
to a compound of formula (VI) as defined above.
The conversion of dithioacetal of formula (XII) to 5-deoxy-L-arabinose of formula (VI) can be carried out by a process comprising the oxidation of a dithioacetal of formula (XII) to obtain a disulfone of formula (XIII)
Figure US08809553-20140819-C00008
in which n is as defined above, and the subsequent reaction with a base.
The oxidation of a dithioacetal of formula (XII) can be carried out with an oxidizing agent for example selected from an organic peracid, preferably metachloro perbenzoic acid, periodic acid or a salt thereof, for example sodium periodate, a peroxysulfate, for example K2SO5, oxone, and hydrogen peroxide, optionally in the presence of a metal catalyst, for example sodium tungstate.
If necessary, the reaction can be carried out in a solvent, which is selected depending on the oxidizing agent, as known to those skilled in the art.
A base, which can be organic or inorganic, strong or weak, is preferably an amine, for example triethylamine or ammonia, more preferably ammonia.
According to a further aspect, the invention provides a process further comprising the conversion of 5-deoxy-L-arabinose of formula (VI), thus obtained, which can optionally be isolated, to L-biopterin of formula (II), or a salt thereof; and, if desired, the subsequent conversion of the latter to Sapropterin of formula (I) or a salt thereof.
The conversion of 5-deoxy-L-arabinose of formula (VI) to L-biopterin of formula (II), can be carried out for example according to Scheme 2 above, or according to Helv. Chim. Acta 1985, 68(6), 1639-1643.
The conversion of L-biopterin of formula (II), or a salt thereof, to Sapropterin of formula (I), or a salt thereof, can be carried out for example by catalytic hydrogenation according to Scheme 1 above.
A salt of L-biopterin of formula (II) or of Sapropterin of formula (I) is preferably a pharmaceutically acceptable salt thereof, for example a salt with an organic or inorganic acid, in particular with hydrochloric acid, typically the dihydrochloride. The salification of L-biopterin of formula (II) or of Sapropterin of formula (I), as well as the conversion of said salts to the respective bases, can be carried out according to known methods.
A dithioacetal of formula (XII) can be prepared by a process comprising the reaction between L-rhamnose, for example commercial, anhydrous or hydrate, with a dithiol of formula (XIV)
Figure US08809553-20140819-C00009
wherein n is 0, 1 or 2, in the presence of a strong acid, and optionally in the presence of a solvent.
Dithiols of formula (XIV) are commercially available. Preferred are those in which n is 1 or 2. Such dithiols in which n is 1 or 2 have only 3 or 4 carbon atoms, like low alkyl thiols, but have higher boiling point, i.e. 169° C. or higher, moreover they do not have pungent smells in spite of their low number of carbon atoms. Thanks to this properties, in particular their low volatility, such dithiols are more suitable than other alkyldithiols for the use on an industrial scale.
A strong acid, which can be organic or inorganic, is preferably a mineral acid, for example aqueous hydrochloric acid.
A solvent, if present, can be a polar aprotic solvent, for example an amide, typically dimethylacetamide, dimethylsulfoxide or acetonitrile; a polar protic solvent, for example water or a C1-C5 alkanol, an ether, for example tetrahydrofuran or dioxane, or a mixture of two or more, preferably 2 or 3, of them.
The reaction can be carried out at a temperature ranging from about 0° C. to the reflux temperature of the solvent, preferably around 20° C.
Dithioacetals of formula (XII) and disulfones of formula (XIII) are novel compounds and are a further object of the invention.
According to a further aspect, the invention provides a process for the preparation of Sapropterin, or a pharmaceutically acceptable salt thereof, which comprises the use of a compound of formula (XII), as herein defined, as the starting material.
The following examples illustrate the invention.
Example 1 Synthesis of (L)-rhamnose 1′,3′-propanedithioacetal (XII; n=1)
L-Rhamnose monohydrate (168.3 g, 0.92 mol) is added as a solid in portions, under strong stirring, to a mixture of 1,3-propanedithiol (100 g, 0.92 mol) in 500 ml of 37% HCl. The resulting solution is kept under stirring for 12 hours at about 20° C. Already at the first hour, formation of an abundant white precipitate is observed. The suspension is then cooled to 5-10° C. and the acid excess is neutralized with NaOH and 500 ml of ice. The suspension at pH of about 7 is then filtered and the solid is washed with water and 100 ml of isopropanol. The wet solid is dried under vacuum at 40° C. for 16 hours to attain 222 g of product (XII) as an off-white solid in 95% yield.
C9H18O4S2; MW=254.27; 1H-NMR (300 MHz, DMSO-d6), δ 5.05 (d, 1H, J=5.7 Hz, OH), 4.42 (d, 1H, J=1.2 Hz, H−1), 4.38 (d, 1H, J=5.4 Hz, OH), 4.22 (d, 1H, J=7.2 Hz, OH), 4.00 (d, 1H, J=8.1 Hz, OH), 3.77-3.68 (m, 2H, H-2, H-5), 3.56-3.51 (m, 1H, H-4), 3.28-3.25 (m, 1H, H-3), 2.96-2.67 (m, 4H, 2×CH 2S), 2.05-1.94 (m, 1H, SCH2CH a), 1.78-1.64 (m, 1H, SCH2CH b), 1.10 (d, 3H, J=6.3 Hz, CH3).
Example 2 Synthesis of 1′,3′-propanedisulfonyl (L)-rhamnose (XIII; n=1)
Sodium tungstate dihydrate (13 g, 0.04 mol) is suspended in a solution obtained by dissolving (L)-rhamnose-1′,3′-propanedithioacetal (XII), (200 g, 0.79 mol) in 1.2 L of glacial acetic acid. The suspension is cooled to about 15° C. and 35% hydrogen peroxide (417 mL, 4.72 mol) is slowly dropped thereinto, keeping the temperature below 40° C. The resulting clear solution is stirred at about 20° C. for 16 hours. The H2O2 excess is then quenched by addition of a sodium thiosulfate concentrated solution. The solvent mixture is then evaporated under reduced pressure to a volume of about 400 mL. The resulting mixture is used directly in the subsequent step, without further purification.
C9H18O8S2; MW=318.37; 1H-NMR (300 MHz, DMSO-d6), δ 6.24 (d, 1H, J=6.9 Hz, OH), 4.82 (d, 1H, J=7.2 Hz, OH), 4.59-4.54 (m, 2H, H−1, OH), 4.45 (d, 1H, J=5.7 Hz, OH), 4.21 (d, 1H, J=8.4 Hz, H-2), 3.63-3.24 (m, 3H, H-5, H-4, H-3), 2.44-2.14 (m, 6H), 1.12 (d, 3H, J=6.0 Hz, CH3).
Example 3 Synthesis of 1′,3′-propanedisulfonyl (L)-rhamnose (XIII; n=1)
(L)-Rhamnose-1′,3′-propanedithioacetal (XII) (200 g; 0.738 mol) and sodium tungstate dihydrate (12.2 g, 0.037 mol) are dissolved in glacial acetic acid (991.6 g). Water (48 g) is added to the resulting solution and the reaction mixture is cooled to 10-15° C. 35% hydrogen peroxide (322.5 g; 3.32 mol) is added in at least 4 hours maintaining the temperature at 20-30° C. The reaction mixture is then heated at about 30-35° C. and maintained under stirring for about 3 hours. Isopropanol (416.7 g) is then added. The resulting suspension is maintained under stirring at 30-35° C. for about 5 hours, then cooled to 20-25° C. in at least 5 hours, subsequently cooled to a 5-10° C. in at least 3 hours and maintained under stirring for another hour. The suspension is cooled and then filtered and the resulting solid is washed with isopropanol (314.2 g).
The product is dried under vacuum at 50° C. for about 24 hours.
209.9 g of product are obtained, as a white solid of formula (XIII), in 88% molar yield.
C9H18O8S2; MW=318.37; 1H-NMR (300 MHz, DMSO-d6), δ 6.24 (d, 1H, J=6.9 Hz, OH), 4.82 (d, 1H, J=7.2 Hz, OH), 4.59-4.54 (m, 2H, H−1, OH), 4.45 (d, 1H, J=5.7 Hz, OH), 4.21 (d, 1H, J=8.4 Hz, H-2), 3.63-3.24 (m, 3H, H-5, H-4, H-3), 2.44-2.14 (m, 6H), 1.12 (d, 3H, J=6.0 Hz, CH3).
Example 4 Synthesis of 5-deoxy-L-arabinose (VI)
The suspension containing disulfone (XIII) from Example 2 is diluted with 1 liter of water and cooled to 10-15° C., then alkalinized to pH of 8-9 with 33% aqueous NH3. A thick suspension immediately forms, which is kept under stirring for 16 hours at about 20° C., until complete disappearance of the starting product. The solid is then filtered and washed with 250 ml of water. The combined aqueous phases are extracted with ethyl acetate to remove any traces of sulfone. The resulting 5-deoxy-(L)-arabinose (VI) aqueous solution can be used as such for the subsequent reaction to obtain L-biopterin and, if desired, Sapropterin.
Example 5 Synthesis of 5-deoxy-L-arabinose (VI)
1′,3′-Propanedisulfonyl (L)-rhamnose (XIII) (209.9 g; 0.650 mol) from Example 3 is dispersed in water (369.9 g) and ethyl acetate (568 g). 28% Ammonia (13.8 g) is then added till a pH higher than or equal to 8.
The reaction mixture is maintained at about 20-25° C. for 1 hour till complete disappearence of the starting product.
The end-reaction suspension is then filtered and resulting solid is washed with water (215 g). The bifase mixture obtained by filtration of the solid and containing 5-deoxy-(L)-arabinose (VI) can be used as such in the subsequent reaction to obtain L-biopterine and, if desired, Sapropterin.

Claims (12)

The invention claimed is:
1. Process for the preparation of 5-deoxy-L-arabinose of formula (VI)
Figure US08809553-20140819-C00010
comprising the conversion of a compound of formula (XII)
Figure US08809553-20140819-C00011
wherein n is 0, 1 or 2;
to a compound of formula (VI) as defined above.
2. Process according to claim 1, wherein the conversion of a compound of formula (XII) to a compound of formula (VI) comprises the oxidation of a dithioacetal of formula (XII) to obtain a disulfone of formula (XIII)
Figure US08809553-20140819-C00012
in which n is as defined in claim 1, and the subsequent reaction with a base.
3. Process according to claim 2, wherein the oxidation of a dithioacetal of formula (XII) is carried out with an oxidizing agent selected from an organic peracid, periodic acid or a salt thereof, a peroxysulfate, oxone, and hydrogen peroxide optionally in the presence of a metal catalyst, preferably sodium tungstate.
4. Process according to claim 2, wherein the base, which can be either organic or inorganic, weak or strong, is preferably an amine or ammonia.
5. Process for the preparation of L-bioterin or a salt thereof, comprising
preparing 5-deoxy-L-arabinose of formula (VI)
Figure US08809553-20140819-C00013
by converting a compound of formula (XII)
Figure US08809553-20140819-C00014
wherein n is 0, 1 or 2;
to a compound of formula (VI) as defined above, and further comprising the conversion of said 5-deoxy-L-arabinose of formula (VI), which can be isolated or not isolated, into L-biopterin, or a salt thereof; and, if desired, its subsequent conversion into Sapropterin, or a salt thereof.
6. Process for the preparation of 5-deoxy-L-arabinose of formula (VI)
Figure US08809553-20140819-C00015
comprising preparing a dithioacetal of formula (XII) by a process comprising the reaction of anhydrous or hydrate L-rhamnose, with a dithiol of formula (XIV)
Figure US08809553-20140819-C00016
in which n is 0, 1 or 2, in the presence of a strong acid, and optionally a solvent, and converting said dithioacetal of formula (XII)
Figure US08809553-20140819-C00017
wherein n is 0, 1 or 2;
to a compound of formula (VI) as defined above.
7. Process according to claim 6, wherein the strong acid, which can be organic or inorganic, is preferably a mineral acid.
8. Process according to claim 6, wherein the solvent is selected from a polar aprotic solvent, preferably an amide, dimethylsulfoxide or acetonitrile; a polar protic solvent, preferably water or a C1-C5 alkanol; an ether, preferably tetrahydrofuran or dioxane; or a mixture of two or more, preferably two or three, of said solvents.
9. A compound of formula (XII)
Figure US08809553-20140819-C00018
wherein n is 1 or 2.
10. A compound of formula (XIII)
Figure US08809553-20140819-C00019
wherein n is 0, 1 or 2.
11. A compound according to claim 9 wherein n is 1.
12. A process for the preparation of L-biopterin or Sapropterin, or a salt thereof, comprising converting a compound of formula (XII),
Figure US08809553-20140819-C00020
wherein n is 0, 1 or 2, into 5-deoxy-L-arabinose of formula (VI)
Figure US08809553-20140819-C00021
then converting the 5-deoxy-L-arabinose of formula (VI) into L-biopterin and/or Sapropterin or a salt thereof.
US13/703,932 2010-06-15 2011-06-13 Process for the preparation of pteridine derivatives Active 2031-07-10 US8809553B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITMI2010A1076 2010-06-15
ITMI2010A001076A IT1400964B1 (en) 2010-06-15 2010-06-15 PROCEDURE FOR THE PREPARATION OF PTERIDINE DERIVATIVES
ITMI2010A001076 2010-06-15
PCT/EP2011/002896 WO2011157388A1 (en) 2010-06-15 2011-06-13 Process for the preparation of pteridine derivatives

Publications (2)

Publication Number Publication Date
US20130090474A1 US20130090474A1 (en) 2013-04-11
US8809553B2 true US8809553B2 (en) 2014-08-19

Family

ID=43332261

Family Applications (1)

Application Number Title Priority Date Filing Date
US13/703,932 Active 2031-07-10 US8809553B2 (en) 2010-06-15 2011-06-13 Process for the preparation of pteridine derivatives

Country Status (9)

Country Link
US (1) US8809553B2 (en)
EP (1) EP2582711B1 (en)
JP (1) JP5972867B2 (en)
CN (1) CN102939298B (en)
AU (1) AU2011267471B8 (en)
ES (1) ES2525357T3 (en)
IT (1) IT1400964B1 (en)
PL (1) PL2582711T3 (en)
WO (1) WO2011157388A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627644B (en) * 2012-04-10 2014-04-16 凯莱英医药集团（天津）股份有限公司 Method for preparing sapropterin dihydrochloride through direct chiral synthesis method
WO2016101211A1 (en) * 2014-12-25 2016-06-30 北京卡威生物医药科技有限公司 Preparation method for sapropterin hydrochloride
CN107353314A (en) * 2016-05-10 2017-11-17 江苏福锌雨医药科技有限公司 A kind of synthetic method of 5- deoxidations-L-arabinose
CN106117097B (en) * 2016-06-20 2017-12-05 四川大学 The preparation method of L rhamnose dialkyl group mercaptal class compounds
CN109776540B (en) * 2017-11-15 2021-07-06 北京启慧生物医药有限公司 Preparation method of sapropterin hydrochloride

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0153095A1 (en) 1984-02-14 1985-08-28 Suntory Limited A process for procuding 5-doxy-L-arabinose
US5502073A (en) * 1987-06-05 1996-03-26 The Wellcome Foundation Heterocyclic pesticidal compounds
EP1849793A1 (en) 2004-12-28 2007-10-31 Asubio Pharma Co., Ltd. Process for producing carbon-diminished aldose compound

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3505329A (en) * 1968-02-06 1970-04-07 Smithkline Corp Process for the synthesis of biopterin
US4713454A (en) 1985-01-28 1987-12-15 Shiratori Pharmaceutical Co., Ltd. Preparation process of (6R)-tetrahydro-L-biopterin
JPS62175495A (en) * 1986-01-27 1987-08-01 Noguchi Kenkyusho Production of sugar dithioacetal derivative
JPH0723367B2 (en) * 1986-02-27 1995-03-15 サントリー株式会社 Oxabicycloheptane derivative
JPH09132589A (en) * 1995-09-08 1997-05-20 Microbial Chem Res Found Fluorine-containing anthracycline derivative having mono- or -di-O-aminoalkanoylation of the hydroxyl group of the sugar moiety

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0153095A1 (en) 1984-02-14 1985-08-28 Suntory Limited A process for procuding 5-doxy-L-arabinose
US5502073A (en) * 1987-06-05 1996-03-26 The Wellcome Foundation Heterocyclic pesticidal compounds
EP1849793A1 (en) 2004-12-28 2007-10-31 Asubio Pharma Co., Ltd. Process for producing carbon-diminished aldose compound

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Fragoso-Serrano M et al: "Conformational analysis of sulfur-containing 6-deoxy-L-hexose derivatives by molecular modeling and NMR spectroscopy. A theoretical study and experimental evidence of intramolecular nonbonded interactions between sulfur and oxygen", Journal of Organic Chemistry 20030919 US, vol. 68, No. 19, Sep. 19, 2003, pp. 7167-7175, XP002614859, ISSN: 0022-3263 p. 7174; compound 3 Chart 1; p. 7168; compound 3.
Greene T.W.; Wuts, P.J.: "Protective groups in organic synthesis", 1999, John Wiley and Sons, XP002614861, pp. 329-344, the whole document.
Khan, A.T.; Mondal, E.; Ghosh, S. ; Islam, S.: "A simple and practical synthetic protocol for acetalisation, thioacetalisation and transthioacetalisation of carbonyl compounds under solvent-free conditions", European Journal Of Organic Chemistry, 2004, pp. 2002-2009, XP002614860, the whole document.
Leung et al. Chem. Abs. DN 149:447691 (2007). *
Taylor et al., "Pteridines. XXXVII. A Total Synthesis of L-erythro-Biopterin and Some Related 6-(Polyhydroxyalkyl) pterins", Journal of the American Chemical Society, 98:8, Apr. 14, 1976, pp. 2301-2307.

Also Published As

Publication number Publication date
US20130090474A1 (en) 2013-04-11
WO2011157388A8 (en) 2012-03-15
ITMI20101076A1 (en) 2011-12-16
CN102939298A (en) 2013-02-20
EP2582711A1 (en) 2013-04-24
CN102939298B (en) 2015-11-25
EP2582711B1 (en) 2014-11-12
JP5972867B2 (en) 2016-08-17
JP2013531654A (en) 2013-08-08
AU2011267471A1 (en) 2013-01-10
PL2582711T3 (en) 2015-04-30
AU2011267471B8 (en) 2014-09-11
IT1400964B1 (en) 2013-07-05
ES2525357T3 (en) 2014-12-22
WO2011157388A1 (en) 2011-12-22
AU2011267471B2 (en) 2014-08-28

Similar Documents

Publication Publication Date Title
US8809553B2 (en) Process for the preparation of pteridine derivatives
JP5027042B2 (en) Crystalline cefdiniric acid addition salt and method for producing cefdinir using the same
KR101832396B1 (en) Method for the synthesis of ergothioneine and the like
EP0222413A2 (en) Novel forskolin derivatives
KR102634384B1 (en) Preparing method of heterocyclic amino acid and their derivatives
KR102570658B1 (en) Preparing method of heterocyclic amino acid and Heterocyclic amino acid by manufactured the method
EP2102172B1 (en) Synthesis of 4-amino-pyrimidines
EP1501838B1 (en) A process for the preparation of clopidogrel
CA2392580A1 (en) A process for the preparation of high purity pemirolast
EP0468445B1 (en) Process for preparation of 6-(substituted-aminopropionyl)-derivates of forskolin
HK1180693A (en) Process for the preparation of pteridine derivatives
CN100418972C (en) Cephe alkene onium salt compound and its preparation and use in preparation of cefepime
EP1678129B1 (en) Improved process for preparing benzhydrylthioacetamide
EP0052959B1 (en) Production of purine derivatives and intermediates therefor
Hansen et al. Preparation of N-Alkyl-N′-4-Pyridylthioureas via Isolable 4-Pyridylisothiocyanate or via Aerial Oxidation of 4-Pyridyldithiocarbamic Acid
CN118063427A (en) Preparation method of 3-hydroxy-2-alkene-1-cyclohexanone derivatives
KR930001116B1 (en) Process for preparing intermediates of cephalosporin derivatives
US6906039B2 (en) Process for preparation of erythromycin compounds
JPH08208594A (en) Production of methylsulfonylaromatic compound by methylatingarylsulfinic acid with methyl chloride
US6916792B2 (en) Process for preparing erythromycin compound
KR20060026121A (en) Method for preparing an amorphous form of a platelet aggregation inhibitory drug
WO2009144263A2 (en) PROCESS FOR OBTAINING 4-HYDROXY-6-METHYL-5, 6-DIHYDRO-4H-THIENO [2,3-b] THIOPYRAN-7, 7-DIOXIDE AND ITS ENANTIOMERS, AND APPLICATIONS THEREOF
JP2002053552A (en) Method for producing 4,6-dimethylindole and derivative thereof
HK1104995A (en) Synthetic method of 5-(2- phenyl)-2-sulfhydryl-1,3,4-thiadiazol
HU226565B1 (en) Process for the production of the amorphous form of clopidogrel hydrogen sulfate

Legal Events

Date Code Title Description
AS Assignment

Owner name: DIPHARMA FRANCIS S.R.L., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ATTOLINO, EMANUELE;MICHIELETTI, MARIO;ROSSI, DAVIDE;AND OTHERS;SIGNING DATES FROM 20121108 TO 20121113;REEL/FRAME:029496/0501

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551)

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8